Back to Search Start Over

Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.

Authors :
Sharma, Ruby
Amdare, Nitin P.
Ghosh, Agnidipta
Schloss, Jennifer
Sidney, John
Garforth, Scott J.
Lopez, Yessenia
Celikgil, Alev
Sette, Alessandro
Almo, Steven C.
DiLorenzo, Teresa P.
Source :
Journal of Biological Chemistry. Sep2024, Vol. 300 Issue 9, p1-14. 14p.
Publication Year :
2024

Abstract

Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B∗39:06, B∗39:01, and B∗38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B∗39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B∗39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B∗39:06 by only two amino acids. HLA-B∗38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B∗39:06 and B∗39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B∗39:06 and B∗39:01 provided an explanation for the distinct peptide C terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B∗38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B∗39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00219258
Volume :
300
Issue :
9
Database :
Academic Search Index
Journal :
Journal of Biological Chemistry
Publication Type :
Academic Journal
Accession number :
180141707
Full Text :
https://doi.org/10.1016/j.jbc.2024.107702